Previous studies have strongly linked lipids and lipoproteins with neurovascular inflammation and dementia. However, the mechanisms and impact of lipid-induced or lipotoxic injury on neurovascular inflammation, microvascular cell death, blood-brain barrier permeability, and cognitive function is not known. This proposal aims to address two important questions about lipotoxic neurovascular injury: 1) What are the cell signaling pathways induced by lipotoxic injury in the brain microvasculature? 2) What are the pathophysiological outcomes of lipotoxic injury to the brain? We will examine cell signaling pathways using brain microvascular endothelial cells and mouse and human brain microvessels. Pathophysiological outcomes will be assessed by measuring brain microvascular cell death, blood brain permeability, and cognitive function. Answering these questions will enable us to develop a better understanding of the development of neurovascular inflammation and point the way to potential therapies for prevention and treatment of vascular dementia. This proposal is innovative because it will investigate the microvascular determinates of neuroinflammation, rather than concentrating only on the neuropathological causes. Also, we plan to use state-of-the-art and novel techniques in this project to examine neurovascular pathophysiology at a level not previously possible. This proposal has a strong translational component in that we will test the concepts developed in cell culture in mouse and human brain microvessels, and mouse models of cognitive impairment. The results of this project could result in a reassessment of blood lipids and lipoproteins in terms of their potential to induce microvascular neuroinflammation and determine if diets that modulate blood fatty acids, rather than lipoproteins, reduce vascular dementia.